Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2.

Published on Apr 21, 2020in eLife7.08
· DOI :10.7554/ELIFE.53353
Adela Constantinescu-Bercu2
Estimated H-index: 2
(Imperial College London),
Luigi Grassi60
Estimated H-index: 60
(University of Cambridge)
+ 3 AuthorsJames T. B. Crawley30
Estimated H-index: 30
(Imperial College London)
Platelet-neutrophil interactions are important for innate immunity, but also contribute to the pathogenesis of deep vein thrombosis, myocardial infarction and stroke. Here we report that, under flow, von Willebrand factor/glycoprotein Iba-dependent platelet 'priming' induces integrin aIIbb3 activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet aIIbb3 to SLC44A2 on neutrophils leads to mechanosensitive-dependent production of highly prothrombotic neutrophil extracellular traps. A polymorphism in SLC44A2 (rs2288904-A) present in 22% of the population causes an R154Q substitution in an extracellular loop of SLC44A2 that is protective against venous thrombosis results in severely impaired binding to both activated aIIbb3 and VWF-primed platelets. This was confirmed using neutrophils homozygous for the SLC44A2 R154Q polymorphism. Taken together, these data reveal a previously unreported mode of platelet-neutrophil crosstalk, mechanosensitive NET production, and provide mechanistic insight into the protective effect of the SLC44A2 rs2288904-A polymorphism in venous thrombosis.
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